25I-NBOMe is significantly more cytotoxic than 2C-I in differentiated SH-SY5Y cells and primary rat cortical cultures, likely due to its higher lipophilicity. Both drugs cause severe mitochondrial dysfunction, including decreased ATP levels and mitochondrial membrane depolarization, without significant changes in reactive oxygen or nitrogen species. 25I-NBOMe also elevates intracellular calcium levels. Apoptosis occurs with both drugs, but 2C-I additionally induces autophagy and strong caspase-3 activation, suggesting caspase-3-dependent apoptosis, while 25I-NBOMe may trigger caspase-3-independent apoptosis through calcium dysregulation and direct mitochondrial damage. Mitochondrial dysfunction and calcium dysregulation are central to the neurotoxicity of these NPS.
Psychedelic phenethylamines, including 2C drugs and their NBOMe derivatives, are new psychoactive substances developed to evade drug control regulations. While psychedelics are traditionally considered to have low addiction potential, recent reports raise concerns. These drugs primarily act on serotonin receptors, especially the 5-HT2A subtype, altering perception, mood, and introspection. They are also linked to adverse effects like cardiovascular problems and neurotoxicity. This review examines the psychedelic pathways of 2C and NBOMe drugs, focusing on their interactions with serotonergic and other neurotransmitter systems and their potential for abuse.
Substituted phenethylamines, including 2C and NBOMe drugs, are potent psychoactive substances with unknown toxicity. In laboratory experiments using rat brain cells and a human cell line, six such drugs (2C-T-2, 2C-T-4, 2C-T-7 and their NBOMe versions) caused concentration-dependent cell death. NBOMe drugs were more toxic than their 2C counterparts, a difference linked to their lipophilicity. The cell damage involved mitochondrial dysfunction, shown by loss of mitochondrial membrane potential and lower ATP levels. Two drugs, 2C-T-7 and 25T7-NBOMe, also disrupted calcium regulation. Although reactive oxygen species did not increase, total glutathione levels fell, indicating oxidative stress. These findings clarify the mechanisms behind these drugs' neurotoxicity.
Sublethal concentrations of the designer drugs 2C-I and 25I-NBOMe impair development and reproductive behavior in the roundworm Caenorhabditis elegans. Exposed worms showed delayed growth and altered egg-laying patterns, indicating that even low, non-lethal doses of these substances can disrupt key biological processes. The findings suggest potential developmental and reproductive risks from these drugs.